A large variety of dosage forms for oral ingestion are known and readily available in the medical field. The most common of these is the tablet. The main limitations of pharmaceutical tablets include poor patient compliance due to difficulty in swallowing and lack of bioavailability of the active through ineffective dissolution of the tablet.
Fast-dissolving dosage forms (FDDFs) are convenient to use and are often used to address issues of patient compliance. There are many forms of FDDFs, for example, “loosely” compressed tablets comprising a large amount of wicking/disintegrating agents, tablets comprising a large amount of effervescent agents, and lyophilized tablets. Most commonly, lyophilized, fast-dissolving dosage forms, which are designed to release the active ingredient in the oral cavity, are formulated using rapidly soluble gelatin-based matrices. These dosage forms are well known and can be used to deliver a wide range of drugs. Most fast-dissolving dosage forms utilize gelatin and mannitol as carriers or matrix forming agents. (Seagar, H., “Drug-Delivery Products and Zydis Fast Dissolving Dosage Form,” J. Pharm. Pharmaco, vol. 50, p. 375-382 (1998)).
FDDFs manufactured by the freeze-drying process such as the Zydis® dosage form are often preferred. They have the distinct advantages of a faster disintegrating time (i.e., less than 5 seconds, as opposed to 1 minute for the loosely compressed tablets), smoother mouth feel (i.e., free of the grittiness associated with the high wicking agents in the compressed tablets), potential for improved pregastric absorption (thereby reduced side effects and improved efficacy for certain medications), and increased storage options.
Typically, gelatin is used to give sufficient strength to the dosage form to prevent breakage during removal from packaging, but once placed in the mouth, the gelatin allows immediate dispersion of the dosage form. Hydrolyzed mammalian gelatin is often the matrix forming agent of choice in FDDFs because it gels rapidly upon cooling. Non-gelling fish gelatin may also be used. During processing, dosed solution/suspension is preferably frozen by passing through a gaseous medium. Thereby, the solution/suspension freezes rapidly, which improves the manufacturing efficiency.
Vaccines, which are important in prophylaxis against disease, exert their effects by provoking an immune response, the effect of which is to prevent infection by the challenging organism, or the onset of the disease processes which would otherwise occur when the antigen against which the immune response has been provoked again challenges a sensitive tissue. Vaccines may also be used therapeutically to modify the nature or level of the immune response to an antigen to allow a host to eliminate a pathogen to which it has already been exposed.
Most existing vaccines are delivered by injection, which is traumatic, inconvenient, expensive and may fail to induce an appropriate immunogenic response in the mucosal tissues. The majority of infections affect, or start, in the mucosal surfaces. Active immunization against these infective agents can depend on the successful induction of a mucosal immune response. Successful mucosal vaccines can both protect the secretory surfaces, i.e., mucosal immunity, and also induce systemic immunity by induction of circulatory antibodies. Mucosal vaccines are also easier to administer to patients and are less expensive to manufacture than conventional vaccines. Delivery by injection does not, of course, directly target the mucosal surfaces or afford the advantages associated with oral vaccines.
The induction of mucosal immunity is evidenced by the appearance of immunoglobulins (Ig), of which IgA antibodies in the mucous overlying the mucosa are particularly significant. IgA exerts multiple effects within the mucosa. Most notably, it acts to neutralize pathogens and components of pathogens, preventing them from accessing and penetrating the underlying epithelial layers, which is what causes an infection. Stimulation of immunity at one mucosal site is known to confer protection to mucous membranes at other sites in the body. Potentially, oral vaccines can be used to induce immunity against oral, gastrointestinal, respiratory, urogenital and ocular pathogens. This ability to generate immunity at sites in the body away from the point of original antigenic stimulation has led to the concept of a common mucosal immune system. There are further indications that stimulation of the mucosal immune system can induce protective circulatory antibodies in the systemic immune system, particularly IgG antibodies. Optimal mucosal vaccines should also induce responses of T lymphocytes, such as the production of T helper cells that can support antibody production, and, for particular pathogens, Th17, Th1, Th2 cells and cytotoxic T lymphocytes (CTL) that act locally and/or systemically.
Vaccines delivered orally can stimulate nasal-associated lymphoid tissue in the mouth and nasopharyngeal region, the lymph nodes, tonsils and adenoids, and gut-associated lymphoid tissue in the Peyer's patches in the small intestine.
Vaccines incorporate antigens which can be peptides, proteins, polysaccharides or whole or partial fragments or extracts of bacteria, viruses or other microorganisms, often attenuated to remove toxic components. In order for vaccines to produce the desired protective effect, exposure to the antigen must be sufficient to provoke an immune response in the recipient. A primary problem in vaccination procedures is ensuring that these antigens or antigenic compounds reach the appropriate site in sufficient quantities to provoke the requisite immune response. There are two aspects of the immune system which can provide the requisite immune response when stimulated by an antigen in a vaccine system: the systemic immune system and the mucosal immune system.
The mucosal immune system consists of areas of inductive and effector lymphoid tissues located in the gastrointestinal tract, the respiratory tract, the genitourinary tract, and the membranes surrounding sensory organs. Inductive sites usually have an organized lymphoid structure and the ability to detect the presence of antigens in the mucosa. Antigen presenting cells at localized areas of lymphoid tissue have the ability to take up absorbed antigen and stimulate T and B cell responses resulting in the production of plasma cells. These plasma cells may reside locally or at effector sites throughout the body secreting antibodies, such as IgA. Secreted IgA molecules resist proteolysis and prevent colonization and entry of pathogens by neutralizing or agglutinating them. In other situations, IgA molecules activate antibody-dependent T cell mediated cytotoxicity, in cases where a pathogen has penetrated the initial barrier. Stimulation of mucosal tissue can also result in the production of other antibody isotypes, such as IgG, IgM, and IgE. These other antibody isotypes may exert effects locally in the mucosa, or have systemic effects, thereby providing additional protection if pathogens manage to penetrate the mucosa. T cell responses induced in the mucosa also can be present at mucosal sites or systemically, which enhances protection of mucosal surfaces and protection against pathogens that penetrate the mucosa.
The principal function of the cells forming the lymphoid tissue is to prevent absorption of pathogens and toxins or to inactivate these pathogens and toxins upon absorption to mucosal tissue. In general, considerably higher doses of antigens are required for mucosal immunization, especially when intended for the oral route. This is due to the existence of effective mechanical and chemical barriers and the degradation and digestion of antigens by enzymes and acids. Additionally, there is a rapid clearance of material from the upper respiratory and digestive tracts to the stomach by mucociliary, peristaltic and secretory processes.
The mucosa has evolved to prevent the induction of effector immune responses against harmless antigens such as foods and inhaled particles. Consequently, many antigens that are introduced at mucosal surfaces induce “tolerance” rather than productive T and B cell responses. Therefore, there is a need to overcome these natural processes in order to make effective vaccines.
Difficulty has been encountered in preparing oral solid dosage forms to deliver vaccines through the mucosal route while at the same time preserving ease of administration and patient comfort. Certain patients that have difficulty swallowing are typically poor candidates for solid oral vaccines with increased physical residency in the oral cavity of the dosage form.
Commercially available oral vaccines are either live attenuated vaccines (e.g., polio, typhoid, rotavirus) or inactivated vaccines (e.g., cholera) and are effective at eliciting an appropriate mucosal immune response since their natural site of infection is the gut mucosa and the vaccine unit triggers the body's natural immune defense mechanisms. However, effective and safe oral vaccines of sub-unit vaccines (containing antigenic fragments of microbes), toxoid vaccines or conjugate vaccines have not yet been established. Oral delivery of these peptide based vaccine strategies are significantly hindered due to their degradation on exposure to the acidic environment of the stomach and proteolytic enzymes that reside in the gastrointestinal tract (GIT). Also, the antigen generally is too large to diffuse across the mucosa of the GIT into the systemic circulation and fails to undergo active transport into the systemic circulation. Therefore, there is often insufficient antigen remaining to illicit either a systemic or mucosal immune response. In addition, a pre-requisite of a mucosal response within the GIT is uptake of the antigens by antigen presenting cells (APCs). The uptake of soluble antigens by the APCs is much less efficient than that of antigen microparticles. Therefore, soluble antigens often fail to achieve an adequate immune response, which can, in fact, lead to tolerance to the antigen.
Various strategies have been employed to protect the antigens from the harsh environment of the GIT and to facilitate a mucosal response. These include enveloping the antigen in liposomes, immunostimulatory complexes (ISCOMs), proteosomes and microparticles. However, such strategies can still require very high doses of antigen to be delivered, along with co-administration of mucosal adjuvants in order to elicit an effective humoral antibody and cell mediated response. Still further, many of the adjuvants under study, such as cholera toxin, are highly toxic in humans. These problems exist regardless of the source of the antigen (bacterial, viral, parasite, etc.).
Accordingly, there exists a need in the pharmaceutical field for improved oral vaccine dosage forms that effectively deliver immunogenic quantities of antigenic preparations and resist chemical and mechanical barriers to antigenic absorption. There further exists a need for solid oral dosage forms that can induce the immune response as effectively as an injectable vaccine while being easy to manufacture and easy and comfortable to administer.
U.S. Patent Application Publication No. 2008-0014260 discloses an oral solid fast-dispersing dosage form for the delivery of vaccines. However, the publication discloses an FDDF comprised of mannitol and gelatin as matrix forming agents. U.S. Pat. No. 6,509,040 teaches a pharmaceutical composition for oral administration in the form of a fast dispersing dosage form essentially free of mammalian gelatin and comprising at least one matrix forming agent and a starch. Neither of these references teaches or suggests the benefits achieved by the present invention, specifically the immune potentiating effect of starch.
The present invention is a novel formulation of FDDF using a starch as an immune response potentiating matrix forming agent, along with optional additional matrix forming agents such as mannitol and gelatin, to stimulate immunity to infection caused by bacteria, viruses, or other microorganisms and achieve better immune response than FDDF formulations known in the art. The immune potentiating effect of starch described in the present invention was not previously disclosed or suggested in the art. Also, the immune potentiating effect can be further enhanced by certain additional matrix forming agents or components, which, too, was not previously disclosed or suggested in the art. This is a significant advancement in the state of the art.